Obesity is the fastest-growing cause of disease and death in America. Seeking diet components that can reduce energy intake becomes an attractive approach to prevent overweight and obesity. Resistant starch is a dietary carbohydrate that resists digestion in the small intestine and is fermented in the large intestine. Our preliminary studies revealed that feeding resistant starch significantly altered energy balance and decreased body fat in rodents. Additionally, resistant starch fed rodents had higher gene expressions for peptide YY (PYY) and proglucagon (a precursor of glucagon-like peptide-1, GLP-1) in the gut, and higher serum levels of PYY and GLP-1 when compared to controls. PYY and GLP-1 are satiety peptides. Administration of either PYY or GLP-1 reduces food intake. Thus, we hypothesize that the decreased body fat is due to increased PYY and/or GLP-1 (PYY/GLP-1) in resistant starch fed animals. The hypothesis will be tested in three specific aims. Specific Aim 1: Determine if PYY and GLP- 1 receptors are required for resistant starch to decrease body fat. This will be achieved by blocking PYY/GLP-1 action through PYY/GLP-1 receptor antagonists or by knocking out of the PYY/GLP-1 receptors. Specific Aim 2: Determine if PYY/GLP-1 decrease body fat via visceral nerves or the brain. The peripheral sites of action for PYY/GLP-1 will be tested by destroying visceral afferent neurons to block signals to the brain. Specific Aim 3: Determine if resistant starch decreases body fat in robust obese animal models. A diet-induced obesity model and a genetic obese model will be used to see if resistant starch can prevent obesity. These experiments will reveal that PYY and GLP-1 are part of the mechanism of resistant starch on reducing body fat. Thus, a simple dietary intervention can increase levels of these peptides and reduce body fat naturally without surgery or pharmaceutical means. The uniqueness of this project is that we will examine nutrient-gene interactions to test a novel concept of diet composition and energy balance. This dietary approach is potentially of great therapeutic importance in the prevention of human obesity. [unreadable] [unreadable] [unreadable]